KRas G12C inhibitors

Abstract

The present disclosure provides compounds of the formula: where R 1 , R 2 , R 3 , R 4 , R 5 , A, and B are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and salts for treating patients for cancer.

What is claimed is: 
     
         1 . A compound of the formula: 
       
         
           
           
               
               
           
         
         wherein:
 A is —OCH 2 —, —N(R 6 )CH 2 —, —OCH 2 CH 2 —, —N(R 6 )CH 2 CH 2 —, —CH 2 OCH 2 —, or —CH 2 N(R 6 )CH 2 —; 
 B is —CH 2 — or —C(O)—; 
 R is —CN, —C(O) C≡CR 8 , or a group of the formula 
 
       
       
         
           
           
               
               
           
         
         
           R 2  is H, methyl, or —CH 2 CN; 
           R 3  and R 5  are each independently H, halogen, cyclopropyl, —C 1-3  alkyl-cyclopropyl, —C 1-6  alkyl optionally substituted 1-3 times with R 10 , or —O—C 1-6  alkyl optionally substituted 1-3 times with R 10 ; 
           R 4  is a group of the formula 
         
       
       
         
           
           
               
               
           
         
         
           R is H, halogen, or —C 1-6  alkyl optionally substituted 1-3 times with R 10 ; 
           R′ is H, or —C 1-6  alkyl; 
           R 6  is H or —C 1-6  alkyl optionally substituted 1-3 times with R 10 ; 
           R 7  is H, halogen, —NR 11 R 12 , —CH 2 NR 11 R 12 , —C 2-6  alkyl optionally substituted 1-3 times with R 10  or —NR 13 R 14 , cyclopropyl, —C 1-3  alkyl cyclopropyl, or —O—C 1-6  alkyl optionally substituted 1-3 times with R 10  or —NR 13 R 14 ; 
           R 8  is H, —C 1-4  alkyl optionally substituted 1-3 times with R 10 , or —C 3-6  cycloalkyl optionally substituted 1-3 times with R 10 ; 
           R 9  is H, halogen, —CN, C 3-6  cycloalkyl, —C 1-3  alkyl-C 3-6  cycloalkyl, or —C 1-6  alkyl optionally substituted 1-3 times with R 10 ; 
           R 10  is independently at each occurrence halogen, oxygen, hydroxy, —C 1-4  alkyl, or —O—C 1-4  alkyl; 
           R 11  and R 12  are each independently H, —C 1-4  alkyl, or —C 1-4  heteroalkyl, wherein R 11  and R 12  may combine to form a C 5-6  heterocycloalkyl; and 
           R 13  and R 14  are each independently H or —C 1-4  alkyl, 
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         2 . The compound according to  claim 1 , wherein A is —OCH 2 CH 2 —, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound according to  claim 1 , wherein B is —C(O)—, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound according to  claim 1 , wherein R 1  is a group of the formula 
       
         
           
           
               
               
           
         
         and wherein R 7  is H, —CHF 2 , —CH 2 F, —CH 2 OH, —CH 2 OCH 3 , —CH 2 N(CH 3 ) 2 , or —CH 2 -morpholine, or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound according to  claim 1 , wherein R 1  is a group of the formula 
       
         
           
           
               
               
           
         
         and wherein R 9  is H, F, Cl, —CHF 2 , —CF 3 , or —CH 2 OH, or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The compound according to  claim 1 , wherein R 2  is H or methyl, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according to  claim 1 , wherein R 3  is H, F, Cl, methyl, methoxy, ethyl, isopropyl, or cyclopropyl or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The compound according to  claim 1 , wherein R is H or F. 
     
     
         9 . The compound according to  claim 1 , wherein R 4  is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound according to  claim 1 , wherein R 5  is H or Cl, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound according to  claim 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         13 . A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to  claim 12 , wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. 
     
     
         14 . A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. 
     
     
         15 . The method according to  claim 14  wherein the cancer is non-small cell lung cancer, and wherein one or more cells express KRas G12C mutant protein. 
     
     
         16 . The method according to  claim 14  wherein the cancer is colorectal cancer, and wherein one or more cells express KRas G12C mutant protein. 
     
     
         17 . The method according to  claim 14  wherein the cancer is pancreatic cancer, and wherein one or more cells express KRas G12C mutant protein. 
     
     
         18 . The method according to  claim 14  wherein the patient has a cancer that was determined to have one or more cells expressing the KRas G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A method of treating a patient with a cancer that has a KRAS G12C mutation comprising administering to a patient in need thereof an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method according to  claim 14 , wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, and or pemetrexed, or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound, or a pharmaceutically acceptable salt thereof, according to  claim 1 , for use in therapy. 
     
     
         22 . The compound, or a pharmaceutically acceptable salt thereof, according to  claim 1 , for use in the treatment of cancer. 
     
     
         23 . The compound, or a pharmaceutically acceptable salt thereof, for use according to  claim 22 , wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. 
     
     
         24 . The compound, or a pharmaceutically acceptable salt thereof, according to  claim 1  for use in simultaneous, separate or sequential combination with one or more of a PD-1 or PD-L1 inhibitor; a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof; an EGFR inhibitor, or a pharmaceutically acceptable salt thereof; an ERK inhibitor, or a pharmaceutically acceptable salt thereof; a platinum agent; and or pemetrexed, or a pharmaceutically acceptable salt thereof, in the treatment of cancer.